This invention relates to water soluble camptothecin analogs, a pharmaceutical composition comprising a tumor cell growth inhibiting amount of such an analog, and a method of inhibiting the growth of tumor cells sensitive to such an analog in an animal in need thereof.
The structure of the DNA helix within eukaryotic cells imposes certain topological problems that the cellular apparatus must solve in order to use its genetic material as a template. The separation of the DNA strands is fundamental to cellular processes such as DNA replication and transcription. Since eukaryotic DNA is organized into chromatin by chromosomal proteins, the ends are constrained and the strands cannot unwind without the aid of enzymes that alter topology. It has long been recognized that the advancement of the transcription or replication complex along the DNA helix would be facilitated by a swivel point which would relieve the torsional strain generated during these processes. Topoisomerases are enzymes that are capable of altering DNA topology in eukaryotic cells. They are critical for important cellular functions and cell proliferation.
There are two classes of topoisomerases in eukaryotic cells, type I and type II. Topoisomerase I is a monomeric enzyme of approximately 100,000 molecular weight. The enzyme binds to DNA and introduces a transient single strand break, unwinds the double helix (or allows it to unwind), and subsequently reseals the break before dissociating from the DNA strand.
Topoisomerase II consists of two identical subunits of molecular weight 170,000. Topoisomerase II transiently breaks both strands of the helix and passes another double-strand segment through the break.
Camptothecin is a water-insoluble, cytotoxic alkaloid produced by Camptotheca accuminata trees indigenous to China and Nothapodytes foetida trees indigenous to India. Camptothecin and a few close congeners thereof are the only class of compounds known to inhibit topoisomerase I.
Inhibition of topoisomerase II is the major target of important commercial oncolytic agents (e.g., etoposide, doxorubicin and mitoxantrone) as well as other oncolytic agents still undergoing development. Camptothecin (and its known congeners) have no effect on topoisomerase II and none of the known topoisomerase II inhibitors has any significant effect on topoisomerase I.
Camptothecin and its known topoisomerase I inhibiting congeners have not proven to be attractive for clinical drug development as cytolytic agents because of lack of clinical efficacy, unacceptable dose limiting toxicity, unpredictable toxicity, poor aqueous solubility, and/or unacceptable shelf life stability. Therefore, there is a need for topoisomerase I inhibiting agents which avoid the undesirable features of camptothecin and its known related topoisomerase I inhibiting congeners. The compounds of this invention fulfill such need.
Miyasaka et al., U.S. Pat. No. 4,604,463, issued Aug. 5, 1986 and assigned to Yakult Honsha, K. K., disclose camptothecin derivatives of the formula: ##STR1## wherein R.sup.1 is a hydrogen atom, a halogen atom or an alkyl group with 1-4 carbon atoms and X is a chlorine atom or where --NR.sup.2 R.sup.3 where R.sup.2 and R.sup.3 are the same or different and each represents a hydrogen atom, a substituted or unsubstituted alkyl group with 1-4 carbon atoms or a substituted or unsubstituted group selected from the group consisting of cyclopentyl, cyclohexyl, N-methylpiperidyl-(4), 2-pyrrolidyl, phenyl, tolyl, xylyl, pyridyl-2 and 2-methylpyridyl-(4), with the proviso that when both R.sup.2 and R.sup.3 are the substituted or unsubstituted alkyl groups, they may be combined together with the nitrogen atom, to which they are bonded, to form a heterocyclic ring selected from the group consisting of pyrrolidine, piperidine, 2-oxapyrrolidine, morpholine, thiomorpholine and 4-R.sup.4 piperidine rings in which R.sup.4 is a hydrogen atom, a substituted or unsubstituted alkyl group with 1-4 carbon atoms or a substituted or unsubstituted phenyl group and wherein the grouping --O--CO--X is bonded atom located in any of the 9-, 10- and 11-positions in the ring A, and ammonium salts or alkali metal salts thereof. Miyasaka et al. also state that such camptothecin derivatives are useful as antitumor medicaments possessing strong antitumor activity with reduced toxicity.
Miyasaka et al., U.S. Pat. No. 4,473,692, issued Sept. 25, 1984 and assigned to Yakult Honsha, K. K., disclose camptothecin derivatives of the formula: ##STR2## wherein R.sup.1 is a hydrogen atom, a straight or branched C.sub.1 --C.sub.30 alkyl group, a C.sub.5 -C.sub.8 hydroxyl group, a C.sub.1 -C.sub.30 alkoxy group or a C.sub.1 -C.sub.17 acyloxy group, R.sup.2 is a hydrogen atom, a straight or branched C.sub.1 -C.sub.30 alkyl group, a C.sub.5 -C.sub.8 cycloalkyl group, a phenylalkyl group, a naphthylalkyl group, a hydroxymethyl group, a carboxymethyl group or a C.sub.1 -C.sub.17 acyloxymethyl group, and R.sup.3 is XR' where R' is a hydrogen atom, a straight or branched C.sub.1 -C.sub.30 alkyl group or a C.sub.1 -C.sub.17 acyl group and X is an oxygen atom or a sulfur atom or wherein R' is a nitro group, an amino group, a C.sub.1 -C.sub.8 alkylamino group, a C.sub.1 -C.sub.17 acylamino group or a halogen atom, with the proviso that when both R.sup.1 and R.sup.2 are hydroqen atoms, R.sup.3 is not hydroxy, methoxy or acetoxy. Miyasaka et al also state that the above camptothecin derivatives have high antitumor activity with slight toxicity.
Miyasaka et al, U.S. Pat. No. 4,545,880, issued Oct. 8, 1985 discloses a method for the preparation of camptothecin derivatives of the formula: ##STR3## wherein R.sup.1 stands for a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxy group or an acyloxy group, R.sup.2 for a hydrogen atom, an alkyl group, an aralkyl group, a hydroxymethyl group, carboxymethyl group or an acyloxymethyl group, R' for a hydrogen atom, an alkyl group or an acyl group and X for an oxygen atom or a sulfur atom.
Yakult Honsha K. K., European Patent Application Publication Number 0,088,642,A2, published Sept. 14, 1983, disclose camptothecin derivatives of the formula: ##STR4## wherein R.sup.1 and R.sup.2 each stands for a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aryl group and R.sup.1 and R.sup.2, taken together with the nitrogen atom to which they are attached, may form a cyclic group. Yakult Honsha, K. K. state that such compounds are useful as pharmaceutical intermediates for antitumor agents.
Wani et al., J. Med. Chem., 29, 2358-2363 (1986), disclose the L-1210 mouse leukemia assay antitumor activity of various camptothecin analogs including 9-nitro-20(S)-camptothecin, 9-amino-20(S)-camptothecin, 9-nitro-10-methoxy-20(S)-camptothecin, 9-amino-10-methoxy-20(S)-camptothecin, 9-nitro-10-hydroxy-20(S)-camptothecin and 9-acetamido-10-hydroxy-20(S)-camptothecin.
Nitta et al., Proc. 14th International Congr. Chemotherapy, Kyoto, 1985, Tokyo Univ., Tokyo Press, Anticancer Section 1, p. 28-30, disclose that a compound called CPT-11 has a profile of activity in preclinical tumor models. CPT 11 is a water soluble camptothecin analog with a 4-(piperidino)-piperidine side chain joined through a carbamate linkage at C-10 of 10-hydroxy-7-ethyl camptothecin.
Although camptothecin is beset by bladder toxicity and unpredictable toxicity to proliferating tissues which preclude its use, 10-hydroxycamptothecin, appears, from the Chinese literature, to retain human solid tumor activity with much reduced toxicity. See, Xu Bin and Yang Jin Long, "Advances in Chinese Medicinal Materials Research", H. M. Chang et al., Eds., World Scientific Publ. Co., Singapore, 1985, p. 377, which discuss the results of Phase I and Phase II clinical trial of 10-hydroxycamptothecin in 253 patients in several types of human solid tumors.
Department of Maxillo facial surgery, 9th People's Hospital, Shanghai, Clin. J. Stomatology, 13, 75 (1978), discusses Phase II clinical trials of camptothecin and 10 hydroxycampothethecin in several types of human solid tumors.
Wani et al., J. Med. Chem., 23, 554 (1980), disclose the synthesis of various synthetic analoqs of camptothecin and 10-hydroxycamptothecin including an analog in which there is a diethylaminoethyl ether at C-10.
Wani et al., J. Med. Chem., 30, 1774 (1987), disclose the synthesis of various 11-substituted camptothecin analogs including cyano, nitro, amino, dimethylamino, formyl, aminomethyl, and hydroxymethyl. Wani et al. report that, among these analogs, only the 11-cyano, 11-nitro and 11-amino camptothecin analogs were active in an assay for antitumor activity. Notably, the 11-aminomethyl analog and its hydrochloride salt were reported to be inactive.